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Showing papers by "Temple University published in 2021"


Journal ArticleDOI
15 Apr 2021-Nature
TL;DR: A newly arisen lineage of SARS-CoV-2 (designated 501Y.V2) was identified in South Africa after the first wave of the epidemic in a severely affected metropolitan area (Nelson Mandela Bay) that is located on the coast of the Eastern Cape province.
Abstract: Continued uncontrolled transmission of SARS-CoV-2 in many parts of the world is creating conditions for substantial evolutionary changes to the virus1,2. Here we describe a newly arisen lineage of SARS-CoV-2 (designated 501Y.V2; also known as B.1.351 or 20H) that is defined by eight mutations in the spike protein, including three substitutions (K417N, E484K and N501Y) at residues in its receptor-binding domain that may have functional importance3-5. This lineage was identified in South Africa after the first wave of the epidemic in a severely affected metropolitan area (Nelson Mandela Bay) that is located on the coast of the Eastern Cape province. This lineage spread rapidly, and became dominant in Eastern Cape, Western Cape and KwaZulu-Natal provinces within weeks. Although the full import of the mutations is yet to be determined, the genomic data-which show rapid expansion and displacement of other lineages in several regions-suggest that this lineage is associated with a selection advantage that most plausibly results from increased transmissibility or immune escape6-8.

1,171 citations


Journal ArticleDOI
TL;DR: In this article, the authors present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes.
Abstract: In 2008, we published the first set of guidelines for standardizing research in autophagy. Since then, this topic has received increasing attention, and many scientists have entered the field. Our knowledge base and relevant new technologies have also been expanding. Thus, it is important to formulate on a regular basis updated guidelines for monitoring autophagy in different organisms. Despite numerous reviews, there continues to be confusion regarding acceptable methods to evaluate autophagy, especially in multicellular eukaryotes. Here, we present a set of guidelines for investigators to select and interpret methods to examine autophagy and related processes, and for reviewers to provide realistic and reasonable critiques of reports that are focused on these processes. These guidelines are not meant to be a dogmatic set of rules, because the appropriateness of any assay largely depends on the question being asked and the system being used. Moreover, no individual assay is perfect for every situation, calling for the use of multiple techniques to properly monitor autophagy in each experimental setting. Finally, several core components of the autophagy machinery have been implicated in distinct autophagic processes (canonical and noncanonical autophagy), implying that genetic approaches to block autophagy should rely on targeting two or more autophagy-related genes that ideally participate in distinct steps of the pathway. Along similar lines, because multiple proteins involved in autophagy also regulate other cellular pathways including apoptosis, not all of them can be used as a specific marker for bona fide autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

1,129 citations


Journal ArticleDOI
TL;DR: In hospitalized patients with Covid-19 pneumonia who were not receiving mechanical ventilation, tocilizumab reduced the likelihood of progression to the composite outcome of mechanical ventilation or death, but it did not improve survival.
Abstract: Background Coronavirus disease 2019 (Covid-19) pneumonia is often associated with hyperinflammation. Despite the disproportionate incidence of Covid-19 among underserved and racial and eth...

986 citations


Journal ArticleDOI
Nuno R. Faria, Thomas A. Mellan1, Charles Whittaker1, Ingra Morales Claro2, Darlan da Silva Candido2, Darlan da Silva Candido3, Swapnil Mishra1, Myuki A E Crispim, Flavia C. S. Sales2, Iwona Hawryluk1, John T. McCrone4, Ruben J.G. Hulswit3, Lucas A M Franco2, Mariana S. Ramundo2, Jaqueline Goes de Jesus2, Pamela S Andrade2, Thais M. Coletti2, Giulia M. Ferreira5, Camila A. M. Silva2, Erika R. Manuli2, Rafael Henrique Moraes Pereira, Pedro S. Peixoto2, Moritz U. G. Kraemer3, Nelson Gaburo, Cecilia da C. Camilo, Henrique Hoeltgebaum1, William Marciel de Souza2, Esmenia C. Rocha2, Leandro Marques de Souza2, Mariana C. Pinho2, Leonardo José Tadeu de Araújo6, Frederico S V Malta, Aline B. de Lima, Joice do P. Silva, Danielle A G Zauli, Alessandro C. S. Ferreira, Ricardo P Schnekenberg3, Daniel J Laydon1, Patrick G T Walker1, Hannah M. Schlüter1, Ana L. P. dos Santos, Maria S. Vidal, Valentina S. Del Caro, Rosinaldo M. F. Filho, Helem M. dos Santos, Renato Santana Aguiar7, José Luiz Proença-Módena8, Bruce Walker Nelson9, James A. Hay10, Melodie Monod1, Xenia Miscouridou1, Helen Coupland1, Raphael Sonabend1, Michaela A. C. Vollmer1, Axel Gandy1, Carlos A. Prete2, Vitor H. Nascimento2, Marc A. Suchard11, Thomas A. Bowden3, Sergei L Kosakovsky Pond12, Chieh-Hsi Wu13, Oliver Ratmann1, Neil M. Ferguson1, Christopher Dye3, Nicholas J. Loman14, Philippe Lemey15, Andrew Rambaut4, Nelson Abrahim Fraiji, Maria Perpétuo Socorro Sampaio Carvalho, Oliver G. Pybus3, Oliver G. Pybus16, Seth Flaxman1, Samir Bhatt1, Samir Bhatt17, Ester Cerdeira Sabino2 
21 May 2021-Science
TL;DR: In this article, the authors used a two-category dynamical model that integrates genomic and mortality data to estimate that P.1 may be 1.7-to 2.4-fold more transmissible and that previous (non-P.1) infection provides 54 to 79% of the protection against infection with P.
Abstract: Cases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in Manaus, Brazil, resurged in late 2020 despite previously high levels of infection. Genome sequencing of viruses sampled in Manaus between November 2020 and January 2021 revealed the emergence and circulation of a novel SARS-CoV-2 variant of concern. Lineage P.1 acquired 17 mutations, including a trio in the spike protein (K417T, E484K, and N501Y) associated with increased binding to the human ACE2 (angiotensin-converting enzyme 2) receptor. Molecular clock analysis shows that P.1 emergence occurred around mid-November 2020 and was preceded by a period of faster molecular evolution. Using a two-category dynamical model that integrates genomic and mortality data, we estimate that P.1 may be 1.7- to 2.4-fold more transmissible and that previous (non-P.1) infection provides 54 to 79% of the protection against infection with P.1 that it provides against non-P.1 lineages. Enhanced global genomic surveillance of variants of concern, which may exhibit increased transmissibility and/or immune evasion, is critical to accelerate pandemic responsiveness.

985 citations


Journal ArticleDOI
TL;DR: The emergence of SARS-CoV-2 variants with novel spike protein mutations that are influencing the epidemiological and clinical aspects of the COVID-19 pandemic has been witnessed as mentioned in this paper.
Abstract: The past several months have witnessed the emergence of SARS-CoV-2 variants with novel spike protein mutations that are influencing the epidemiological and clinical aspects of the COVID-19 pandemic. These variants can increase rates of virus transmission and/or increase the risk of reinfection and reduce the protection afforded by neutralizing monoclonal antibodies and vaccination. These variants can therefore enable SARS-CoV-2 to continue its spread in the face of rising population immunity while maintaining or increasing its replication fitness. The identification of four rapidly expanding virus lineages since December 2020, designated variants of concern, has ushered in a new stage of the pandemic. The four variants of concern, the Alpha variant (originally identified in the UK), the Beta variant (originally identified in South Africa), the Gamma variant (originally identified in Brazil) and the Delta variant (originally identified in India), share several mutations with one another as well as with an increasing number of other recently identified SARS-CoV-2 variants. Collectively, these SARS-CoV-2 variants complicate the COVID-19 research agenda and necessitate additional avenues of laboratory, epidemiological and clinical research.

593 citations


Journal ArticleDOI
01 Mar 2021-Chest
TL;DR: A systematic review and meta-analysis of 15 standard and COVID-19 specific sources found the overall estimated pooled incidence of VTE was 17.0%, with higher rates with routine screening, inclusion of distal DVT and subsegmental PE, in critically ill patients, and in prospective studies.

347 citations


Journal ArticleDOI
TL;DR: An overview of the management of patients with COPD during the COVID-19 pandemic is presented and inhaled corticosteroids, long-acting bronchodilators, roflumilast, or chronic macrolides should be used as indicated for stable COPD management.
Abstract: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has raised many questions about the management of patients with chronic obstructive pulmonary disease (COPD) and whether modifications of their therapy are required. It has raised questions about recognizing and differentiating coronavirus disease (COVID-19) from COPD given the similarity of the symptoms. The Global Initiative for Chronic Obstructive Lung Disease (GOLD) Science Committee used established methods for literature review to present an overview of the management of patients with COPD during the COVID-19 pandemic. It is unclear whether patients with COPD are at increased risk of becoming infected with SARS-CoV-2. During periods of high community prevalence of COVID-19, spirometry should only be used when it is essential for COPD diagnosis and/or to assess lung function status for interventional procedures or surgery. Patients with COPD should follow basic infection control measures, including social distancing, hand washing, and wearing a mask or face covering. Patients should remain up to date with appropriate vaccinations, particularly annual influenza vaccination. Although data are limited, inhaled corticosteroids, long-acting bronchodilators, roflumilast, or chronic macrolides should continue to be used as indicated for stable COPD management. Systemic steroids and antibiotics should be used in COPD exacerbations according to the usual indications. Differentiating symptoms of COVID-19 infection from chronic underlying symptoms or those of an acute COPD exacerbation may be challenging. If there is suspicion for COVID-19, testing for SARS-CoV-2 should be considered. Patients who developed moderate-to-severe COVID-19, including hospitalization and pneumonia, should be treated with evolving pharmacotherapeutic approaches as appropriate, including remdesivir, dexamethasone, and anticoagulation. Managing acute respiratory failure should include appropriate oxygen supplementation, prone positioning, noninvasive ventilation, and protective lung strategy in patients with COPD and severe acute respiratory distress syndrome. Patients who developed asymptomatic or mild COVID-19 should be followed with the usual COPD protocols. Patients who developed moderate or worse COVID-19 should be monitored more frequently and accurately than the usual patients with COPD, with particular attention to the need for oxygen therapy.

345 citations


Journal ArticleDOI
02 Apr 2021-Science
TL;DR: In this article, the authors present 64 assembled haplotypes from 32 diverse human genomes, which integrate all forms of genetic variation, even across complex loci, and identify 107,590 structural variants (SVs), of which 68% were not discovered with short-read sequencing.
Abstract: Long-read and strand-specific sequencing technologies together facilitate the de novo assembly of high-quality haplotype-resolved human genomes without parent-child trio data. We present 64 assembled haplotypes from 32 diverse human genomes. These highly contiguous haplotype assemblies (average minimum contig length needed to cover 50% of the genome: 26 million base pairs) integrate all forms of genetic variation, even across complex loci. We identified 107,590 structural variants (SVs), of which 68% were not discovered with short-read sequencing, and 278 SV hotspots (spanning megabases of gene-rich sequence). We characterized 130 of the most active mobile element source elements and found that 63% of all SVs arise through homology-mediated mechanisms. This resource enables reliable graph-based genotyping from short reads of up to 50,340 SVs, resulting in the identification of 1526 expression quantitative trait loci as well as SV candidates for adaptive selection within the human population.

289 citations


Journal ArticleDOI
TL;DR: In this paper, the authors present an overview of adipose tissue inflammation by highlighting the most recent reports in the scientific literature and summarizing their overall understanding of the field, and discuss key endogenous anti-inflammatory mediators and analyze their mechanistic role(s) in the pathogenesis and treatment of inflammatory tissue.
Abstract: Several lines of preclinical and clinical research have confirmed that chronic low-grade inflammation of adipose tissue is mechanistically linked to metabolic disease and organ tissue complications in the overweight and obese organism. Despite this widely confirmed paradigm, numerous open questions and knowledge gaps remain to be investigated. This is mainly due to the intricately intertwined cross-talk of various pro- and anti-inflammatory signaling cascades involved in the immune response of expanding adipose depots, particularly the visceral adipose tissue. Adipose tissue inflammation is initiated and sustained over time by dysfunctional adipocytes that secrete inflammatory adipokines and by infiltration of bone marrow-derived immune cells that signal via production of cytokines and chemokines. Despite its low-grade nature, adipose tissue inflammation negatively impacts remote organ function, a phenomenon that is considered causative of the complications of obesity. The aim of this review is to broadly present an overview of adipose tissue inflammation by highlighting the most recent reports in the scientific literature and summarizing our overall understanding of the field. We also discuss key endogenous anti-inflammatory mediators and analyze their mechanistic role(s) in the pathogenesis and treatment of adipose tissue inflammation. In doing so, we hope to stimulate studies to uncover novel physiological, cellular, and molecular targets for the treatment of obesity.

280 citations


Journal ArticleDOI
19 Apr 2021
TL;DR: An overview of control schemes for GFM converters is provided in this paper, where the authors identify the main subsystems in respect to their functionalities and derive a generalized control structure for each of them.
Abstract: In the last decade, the concept of grid-forming (GFM) converters has been introduced for microgrids and islanded power systems. Recently, the concept has been proposed for use in wider interconnected transmission networks, and several control structures have thus been developed, giving rise to discussions about the expected behaviour of such converters. In this paper, an overview of control schemes for GFM converters is provided. By identifying the main subsystems in respect to their functionalities, a generalized control structure is derived and different solutions for each of the main subsystems composing the controller are analyzed and compared. Subsequently, several selected open issues and challenges regarding GFM converters, i. e. angle stability, fault ride-through (FRT) capabilities, and transition from islanded to grid connected mode are discussed. Perspectives on challenges and future trends are lastly shared.

257 citations


Journal ArticleDOI
TL;DR: A new framework model based on a novel feature selection metric approach named CorrAUC is proposed, and a new feature selection algorithm based on the wrapper technique to filter the features accurately and select effective features for the selected ML algorithm by using the area under the curve (AUC) metric.
Abstract: Identification of anomaly and malicious traffic in the Internet-of-Things (IoT) network is essential for the IoT security to keep eyes and block unwanted traffic flows in the IoT network. For this purpose, numerous machine-learning (ML) technique models are presented by many researchers to block malicious traffic flows in the IoT network. However, due to the inappropriate feature selection, several ML models prone misclassify mostly malicious traffic flows. Nevertheless, the significant problem still needs to be studied more in-depth that is how to select effective features for accurate malicious traffic detection in the IoT network. To address the problem, a new framework model is proposed. First, a novel feature selection metric approach named CorrAUC is proposed, and then based on CorrAUC, a new feature selection algorithm named CorrAUC is developed and designed, which is based on the wrapper technique to filter the features accurately and select effective features for the selected ML algorithm by using the area under the curve (AUC) metric. Then, we applied the integrated TOPSIS and Shannon entropy based on a bijective soft set to validate selected features for malicious traffic identification in the IoT network. We evaluate our proposed approach by using the Bot-IoT data set and four different ML algorithms. The experimental results analysis showed that our proposed method is efficient and can achieve >96% results on average.

Journal ArticleDOI
D. Adhikari1, H. Albataineh2, Darko Androić3, K. A. Aniol4, D. S. Armstrong5, T. Averett5, C. Ayerbe Gayoso5, S. Barcus6, V. Bellini7, R. S. Beminiwattha8, Jay Benesch6, H. Bhatt9, D. Bhatta Pathak8, D. Bhetuwal9, B. Blaikie10, Q. Campagna5, A. Camsonne6, G. D. Cates11, Y. Chen8, C. Clarke12, J. C. Cornejo13, S. Covrig Dusa6, P. Datta14, A. Deshpande12, Dipangkar Dutta9, C. Feldman12, E. Fuchey14, C. Gal12, C. Gal11, D. Gaskell6, T. Gautam15, Michael Gericke10, C. Ghosh16, C. Ghosh12, I. Halilovic10, J. O. Hansen6, F. Hauenstein17, W. Henry18, Charles Horowitz19, C. Jantzi11, Siyu Jian11, S. Johnston16, D. C. Jones18, B. Karki20, S. Katugampola11, Cynthia Keppel6, P. M. King20, D. King21, M. Knauss22, K. S. Kumar16, T. Kutz12, N. Lashley-Colthirst15, G. Leverick10, H. Liu16, N. Liyange11, S. Malace6, R. Mammei23, Juliette Mammei10, M. McCaughan6, D. McNulty1, D. G. Meekins6, C. Metts5, R. Michaels6, M. M. Mondal12, Jim Napolitano18, A. Narayan24, D. Nikolaev18, M. N. H. Rashad17, V. Owen5, C. Palatchi11, J. Pan10, B. Pandey15, S. Park12, Kent Paschke11, M. Petrusky12, Michael Pitt25, S. Premathilake11, Andrew Puckett14, B. P. Quinn13, R. W. Radloff20, S. Rahman10, A. Rathnayake11, Brendan Reed19, P. E. Reimer26, R. Richards12, S. Riordan26, Y. Roblin6, S. Seeds14, A. Shahinyan27, Paul Souder21, L. G. Tang15, L. G. Tang6, Michaela Thiel28, Y. Tian21, G. M. Urciuoli, E. W. Wertz5, Bogdan Wojtsekhowski6, B. Yale5, T. Ye12, A. Yoon29, A. Zec11, W. Zhang12, Jiawen Zhang12, Jiawen Zhang30, X. Zheng11 
TL;DR: In this paper, the parity-violating asymmetry in the elastic scattering of longitudinally polarized electrons from 208 Pb was measured, leading to an extraction of the neutral weak form factor F = 0.0036(exp)±0.0013(theo)
Abstract: We report a precision measurement of the parity-violating asymmetry A_{PV} in the elastic scattering of longitudinally polarized electrons from ^{208}Pb. We measure A_{PV}=550±16(stat)±8(syst) parts per billion, leading to an extraction of the neutral weak form factor F_{W}(Q^{2}=0.00616 GeV^{2})=0.368±0.013. Combined with our previous measurement, the extracted neutron skin thickness is R_{n}-R_{p}=0.283±0.071 fm. The result also yields the first significant direct measurement of the interior weak density of ^{208}Pb: ρ_{W}^{0}=-0.0796±0.0036(exp)±0.0013(theo) fm^{-3} leading to the interior baryon density ρ_{b}^{0}=0.1480±0.0036(exp)±0.0013(theo) fm^{-3}. The measurement accurately constrains the density dependence of the symmetry energy of nuclear matter near saturation density, with implications for the size and composition of neutron stars.

Journal ArticleDOI
TL;DR: The Concise Guide to PHARMACOLOGY 2021/22 as mentioned in this paper provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands.
Abstract: The Concise Guide to PHARMACOLOGY 2021/22 is the fifth in this series of biennial publications. The Concise Guide provides concise overviews, mostly in tabular format, of the key properties of nearly 1900 human drug targets with an emphasis on selective pharmacology (where available), plus links to the open access knowledgebase source of drug targets and their ligands (www.guidetopharmacology.org), which provides more detailed views of target and ligand properties. Although the Concise Guide constitutes over 500 pages, the material presented is substantially reduced compared to information and links presented on the website. It provides a permanent, citable, point-in-time record that will survive database updates. The full contents of this section can be found at http://onlinelibrary.wiley.com/doi/bph.15538. G protein-coupled receptors are one of the six major pharmacological targets into which the Guide is divided, with the others being: ion channels, nuclear hormone receptors, catalytic receptors, enzymes and transporters. These are presented with nomenclature guidance and summary information on the best available pharmacological tools, alongside key references and suggestions for further reading. The landscape format of the Concise Guide is designed to facilitate comparison of related targets from material contemporary to mid-2021, and supersedes data presented in the 2019/20, 2017/18, 2015/16 and 2013/14 Concise Guides and previous Guides to Receptors and Channels. It is produced in close conjunction with the Nomenclature and Standards Committee of the International Union of Basic and Clinical Pharmacology (NC-IUPHAR), therefore, providing official IUPHAR classification and nomenclature for human drug targets, where appropriate.

Journal ArticleDOI
TL;DR: A new benchmark, called DHF1K (Dynamic Human Fixation 1K), is introduced, for predicting fixations during dynamic scene free-viewing, and a novel video saliency model is proposed, called ACLNet (Attentive CNN-LSTM Network), that augments the CNN- LSTM architecture with a supervised attention mechanism to enable fast end-to-end saliency learning.
Abstract: Predicting where people look in static scenes, a.k.a visual saliency, has received significant research interest recently. However, relatively less effort has been spent in understanding and modeling visual attention over dynamic scenes. This work makes three contributions to video saliency research. First, we introduce a new benchmark, called DHF1K (Dynamic Human Fixation 1K), for predicting fixations during dynamic scene free-viewing, which is a long-time need in this field. DHF1K consists of 1K high-quality elaborately-selected video sequences annotated by 17 observers using an eye tracker device. The videos span a wide range of scenes, motions, object types and backgrounds. Second, we propose a novel video saliency model, called ACLNet (Attentive CNN-LSTM Network), that augments the CNN-LSTM architecture with a supervised attention mechanism to enable fast end-to-end saliency learning. The attention mechanism explicitly encodes static saliency information, thus allowing LSTM to focus on learning a more flexible temporal saliency representation across successive frames. Such a design fully leverages existing large-scale static fixation datasets, avoids overfitting, and significantly improves training efficiency and testing performance. Third, we perform an extensive evaluation of the state-of-the-art saliency models on three datasets : DHF1K, Hollywood-2, and UCF sports. An attribute-based analysis of previous saliency models and cross-dataset generalization are also presented. Experimental results over more than 1.2K testing videos containing 400K frames demonstrate that ACLNet outperforms other contenders and has a fast processing speed (40 fps using a single GPU). Our code and all the results are available at https://github.com/wenguanwang/DHF1K .

Journal ArticleDOI
Angela B. Brueggemann1, Melissa J. Jansen van Rensburg1, David Shaw1, Noel D. McCarthy2, Keith A. Jolley1, Martin C. J. Maiden1, Mark van der Linden3, Zahin Amin-Chowdhury4, Desiree E. Bennett5, Ray Borrow6, Maria Cristina C. Brandileone, Karen Broughton4, Ruth Campbell, Bin Cao7, Carlo Casanova8, Eun Hwa Choi9, Yiu Wai Chu10, Stephen Clark6, Heike Claus11, Juliana Coelho4, Mary Corcoran12, Mary Corcoran13, Simon Cottrell14, Robert Cunney12, Robert Cunney13, Tine Dalby15, Heather Davies, Linda de Gouveia16, Ala Eddine Deghmane17, Walter Demczuk18, Stefanie Desmet19, Richard J. Drew12, Richard J. Drew13, Mignon du Plessis16, Helga Erlendsdóttir, Norman K. Fry4, Kurt Fuursted15, Steve J. Gray6, Birgitta Henriques-Normark20, Thomas Hale1, Markus Hilty8, Steen Hoffmann15, Hilary Humphreys5, Margaret Ip21, Susanne Jacobsson22, Jillian Johnston, Jana Kozakova, Karl G. Kristinsson, Pavla Krizova, Alicja Kuch, Shamez N Ladhani4, Thiên Trí Lâm11, Vera Lebedova, Laura Lindholm23, David Litt4, Irene Martin18, Delphine Martiny24, Wesley Mattheus, Martha McElligott5, Mary Meehan5, Susan Meiring16, Paula Mölling22, Eva Morfeldt25, Julie Morgan, Robert M. Mulhall5, Carmen Muñoz-Almagro26, David R. Murdoch27, Joy Murphy, Martin Musilek, Alexandre Mzabi, Amaresh Perez-Argüello26, Monique Perrin, Malorie Perry14, Alba Redin26, Richard J. Roberts14, Maria Roberts14, Assaf Rokney28, Merav Ron28, Kevin J. Scott, Carmen L. Sheppard4, Lotta Siira23, Anna Skoczynska, Monica Sloan, Hans Christian Slotved15, Andrew Smith, Joon Young Song29, Muhamed-Kheir Taha17, Maija Toropainen23, Dominic N.C. Tsang10, Anni Vainio23, Nina M. van Sorge30, Emmanuelle Varon, Jiri Vlach, Ulrich Vogel11, Sandra Vohrnova, Anne von Gottberg16, Rosemeire C. Zanella, Fei Zhou7 
01 Jun 2021
TL;DR: In this article, the authors investigated the incidence of invasive disease due to these pathogens during the early months of the COVID-19 pandemic and found that containment policies and public information campaigns likely reduced transmission of S pneumoniae, H influenzae, and N meningitidis, leading to a significant reduction in lifethreatening invasive diseases in many countries worldwide.
Abstract: Summary Background Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis, which are typically transmitted via respiratory droplets, are leading causes of invasive diseases, including bacteraemic pneumonia and meningitis, and of secondary infections subsequent to post-viral respiratory disease. The aim of this study was to investigate the incidence of invasive disease due to these pathogens during the early months of the COVID-19 pandemic. Methods In this prospective analysis of surveillance data, laboratories in 26 countries and territories across six continents submitted data on cases of invasive disease due to S pneumoniae, H influenzae, and N meningitidis from Jan 1, 2018, to May, 31, 2020, as part of the Invasive Respiratory Infection Surveillance (IRIS) Initiative. Numbers of weekly cases in 2020 were compared with corresponding data for 2018 and 2019. Data for invasive disease due to Streptococcus agalactiae, a non-respiratory pathogen, were collected from nine laboratories for comparison. The stringency of COVID-19 containment measures was quantified using the Oxford COVID-19 Government Response Tracker. Changes in population movements were assessed using Google COVID-19 Community Mobility Reports. Interrupted time-series modelling quantified changes in the incidence of invasive disease due to S pneumoniae, H influenzae, and N meningitidis in 2020 relative to when containment measures were imposed. Findings 27 laboratories from 26 countries and territories submitted data to the IRIS Initiative for S pneumoniae (62 434 total cases), 24 laboratories from 24 countries submitted data for H influenzae (7796 total cases), and 21 laboratories from 21 countries submitted data for N meningitidis (5877 total cases). All countries and territories had experienced a significant and sustained reduction in invasive diseases due to S pneumoniae, H influenzae, and N meningitidis in early 2020 (Jan 1 to May 31, 2020), coinciding with the introduction of COVID-19 containment measures in each country. By contrast, no significant changes in the incidence of invasive S agalactiae infections were observed. Similar trends were observed across most countries and territories despite differing stringency in COVID-19 control policies. The incidence of reported S pneumoniae infections decreased by 68% at 4 weeks (incidence rate ratio 0·32 [95% CI 0·27–0·37]) and 82% at 8 weeks (0·18 [0·14–0·23]) following the week in which significant changes in population movements were recorded. Interpretation The introduction of COVID-19 containment policies and public information campaigns likely reduced transmission of S pneumoniae, H influenzae, and N meningitidis, leading to a significant reduction in life-threatening invasive diseases in many countries worldwide. Funding Wellcome Trust (UK), Robert Koch Institute (Germany), Federal Ministry of Health (Germany), Pfizer, Merck, Health Protection Surveillance Centre (Ireland), SpID-Net project (Ireland), European Centre for Disease Prevention and Control (European Union), Horizon 2020 (European Commission), Ministry of Health (Poland), National Programme of Antibiotic Protection (Poland), Ministry of Science and Higher Education (Poland), Agencia de Salut Publica de Catalunya (Spain), Sant Joan de Deu Foundation (Spain), Knut and Alice Wallenberg Foundation (Sweden), Swedish Research Council (Sweden), Region Stockholm (Sweden), Federal Office of Public Health of Switzerland (Switzerland), and French Public Health Agency (France).

Journal ArticleDOI
TL;DR: In this paper, a randomized, cross-sectional study was performed to investigate the side effects of the BNT162b2 vaccine using an independent online questionnaire gathering responses from healthcare workers (HCWs) with detailed review of organ systems.

Journal ArticleDOI
TL;DR: In this paper, the efficacy of artemether-lumefantrine and genetic characterisation of Pfkelch13 alleles and their association with treatment outcomes were investigated in three Rwandan sites: Masaka, Rukara, and Bugarama.
Abstract: Summary Background Partial artemisinin resistance is suspected if delayed parasite clearance (ie, persistence of parasitaemia on day 3 after treatment initiation) is observed. Validated markers of artemisinin partial resistance in southeast Asia, Plasmodium falciparum kelch13 (Pfkelch13) R561H and P574L, have been reported in Rwanda but no association with parasite clearance has been observed. We aimed to establish the efficacy of artemether–lumefantrine and genetic characterisation of Pfkelch13 alleles and their association with treatment outcomes. Methods This open-label, single-arm, multicentre, therapeutic efficacy study was done in 2018 in three Rwandan sites: Masaka, Rukara, and Bugarama. Children aged 6–59 months with P falciparum monoinfection and fever were eligible and treated with a 3-day course of artemether–lumefantrine. Treatment response was monitored for 28 days using weekly microscopy screenings of blood samples for P falciparum. Mutations in Pfkelch13 and P falciparum multidrug resistance-1 (Pfmdr1) genes were characterised in parasites collected from enrolled participants. Analysis of flanking microsatellites surrounding Pfkelch13 was done to define the origins of the R561H mutations. The primary endpoint was PCR-corrected parasitological cure on day 28, as per WHO protocol. Findings 228 participants were enrolled and 224 (98·2%) reached the study endpoint. PCR-corrected efficacies were 97·0% (95% CI 88–100) in Masaka, 93·8% (85–98) in Rukara, and 97·2% (91–100) in Bugarama. Pfkelch13 R561H mutations were present in 28 (13%) of 218 pre-treatment samples and P574L mutations were present in two (1%) pre-treatment samples. 217 (90%) of the 240 Pfmdr1 haplotypes observed in the pretreatment samples, had either the NFD (N86Y, Y184F, D1246Y) or NYD haplotype. Eight (16%) of 51 participants in Masaka and 12 (15%) of 82 participants in Rukara were microscopically positive 3 days after treatment initiation, which was associated with pre-treatment presence of Pfkelch13 R561H in Masaka (p=0·0005). Genetic analysis of Pfkelch13 R561H mutations suggest their common ancestry and local origin in Rwanda. Interpretation We confirm evidence of emerging artemisinin partial resistance in Rwanda. Although artemether–lumefantrine remains efficacious, vigilance for decreasing efficacy, further characterisation of artemisinin partial resistance, and evaluation of additional antimalarials in Rwanda should be considered. Funding The US President's Malaria Initiative. Translation For the French translation of the abstract see Supplementary Materials section.

Journal ArticleDOI
TL;DR: New early predictive criteria for COVID-19-associated cytokine storm is proposed, with sensitivity and specificity of 0.85 and 0.80, which can be readily used in clinical practice to determine the need for an early therapeutic regimen, block the hyperimmune response and possibly decrease mortality.
Abstract: Objectives To develop predictive criteria for COVID-19-associated cytokine storm (CS), a severe hyperimmune response that results in organ damage in some patients infected with COVID-19. We hypothesised that criteria for inflammation and cell death would predict this type of CS. Methods We analysed 513 hospitalised patients who were positive for COVID-19 reverse transcriptase PCR and for ground-glass opacity by chest high-resolution CT. To achieve an early diagnosis, we analysed the laboratory results of the first 7 days of hospitalisation. We implemented logistic regression and principal component analysis to determine the predictive criteria. We used a ‘genetic algorithm’ to derive the cut-offs for each laboratory result. We validated the criteria with a second cohort of 258 patients. Results We found that the criteria for macrophage activation syndrome, haemophagocytic lymphohistiocytosis and the HScore did not identify the COVID-19 cytokine storm (COVID-CS). We developed new predictive criteria, with sensitivity and specificity of 0.85 and 0.80, respectively, comprising three clusters of laboratory results that involve (1) inflammation, (2) cell death and tissue damage, and (3) prerenal electrolyte imbalance. The criteria identified patients with longer hospitalisation and increased mortality. These results highlight the relevance of hyperinflammation and tissue damage in the COVID-CS. Conclusions We propose new early predictive criteria to identify the CS occurring in patients with COVID-19. The criteria can be readily used in clinical practice to determine the need for an early therapeutic regimen, block the hyperimmune response and possibly decrease mortality.

Posted ContentDOI
Nuno R. Faria1, Nuno R. Faria2, Nuno R. Faria3, Thomas A. Mellan1, Charles Whittaker1, Ingra Morales Claro3, Darlan da Silva Candido3, Darlan da Silva Candido2, Swapnil Mishra1, Myuki A E Crispim, Flavia C. S. Sales3, Iwona Hawryluk1, John T. McCrone4, Ruben J.G. Hulswit2, Lucas A M Franco3, Mariana S. Ramundo3, Jaqueline Goes de Jesus3, Pamela S Andrade3, Thais M. Coletti3, Giulia M. Ferreira5, Camila A. M. Silva3, Erika R. Manuli3, Rafael Henrique Moraes Pereira, Pedro S. Peixoto3, Moritz U. G. Kraemer2, Nelson Gaburo, Cecilia da C. Camilo, Henrique Hoeltgebaum1, William Marciel de Souza3, Esmenia C. Rocha3, Leandro Marques de Souza3, Mariana C. Pinho3, Leonardo José Tadeu de Araújo6, Frederico S V Malta, Aline B. de Lima, Joice do P. Silva, Danielle A G Zauli, Alessandro C. S. Ferreira, Ricardo P Schnekenberg2, Daniel J Laydon1, Patrick G T Walker1, Hannah M. Schlüter1, Ana L. P. dos Santos, Maria S. Vidal, Valentina S. Del Caro, Rosinaldo M. F. Filho, Helem M. dos Santos, Renato Santana Aguiar7, José Luiz Proença Modena8, Bruce Walker Nelson9, James A. Hay10, Melodie Monod1, Xenia Miscouridou1, Helen Coupland1, Raphael Sonabend1, Michaela A. C. Vollmer1, Axel Gandy1, Marc A. Suchard11, Thomas A. Bowden2, Sergei L Kosakovsky Pond12, Chieh-Hsi Wu13, Oliver Ratmann1, Neil M. Ferguson1, Christopher Dye2, Nicholas J. Loman14, Philippe Lemey15, Andrew Rambaut4, Nelson Abrahim Fraiji, Maria Perpétuo Socorro Sampaio Carvalho, Oliver G. Pybus16, Oliver G. Pybus2, Seth Flaxman1, Samir Bhatt17, Samir Bhatt1, Ester Cerdeira Sabino3 
03 Mar 2021-medRxiv
TL;DR: In this paper, the emergence and circulation of a new SARS-CoV-2 variant of concern, lineage P.1, that acquired 17 mutations, including a trio in the spike protein (K417T, E484K and N501Y) associated with increased binding to the human ACE2 receptor.
Abstract: Cases of SARS-CoV-2 infection in Manaus, Brazil, resurged in late 2020, despite high levels of previous infection there. Through genome sequencing of viruses sampled in Manaus between November 2020 and January 2021, we identified the emergence and circulation of a novel SARS-CoV-2 variant of concern, lineage P.1, that acquired 17 mutations, including a trio in the spike protein (K417T, E484K and N501Y) associated with increased binding to the human ACE2 receptor. Molecular clock analysis shows that P.1 emergence occurred around early November 2020 and was preceded by a period of faster molecular evolution. Using a two-category dynamical model that integrates genomic and mortality data, we estimate that P.1 may be 1.4–2.2 times more transmissible and 25-61% more likely to evade protective immunity elicited by previous infection with non-P.1 lineages. Enhanced global genomic surveillance of variants of concern, which may exhibit increased transmissibility and/or immune evasion, is critical to accelerate pandemic responsiveness. One-Sentence Summary We report the evolution and emergence of a SARS-CoV-2 lineage of concern associated with rapid transmission in Manaus.

Journal ArticleDOI
TL;DR: In this paper, the authors assess the types of natural selection taking place in Sarbecoviruses in horseshoe bats versus the early SARS-CoV-2 evolution in humans.
Abstract: Virus host shifts are generally associated with novel adaptations to exploit the cells of the new host species optimally. Surprisingly, Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has apparently required little to no significant adaptation to humans since the start of the Coronavirus Disease 2019 (COVID-19) pandemic and to October 2020. Here we assess the types of natural selection taking place in Sarbecoviruses in horseshoe bats versus the early SARS-CoV-2 evolution in humans. While there is moderate evidence of diversifying positive selection in SARS-CoV-2 in humans, it is limited to the early phase of the pandemic, and purifying selection is much weaker in SARS-CoV-2 than in related bat Sarbecoviruses. In contrast, our analysis detects evidence for significant positive episodic diversifying selection acting at the base of the bat virus lineage SARS-CoV-2 emerged from, accompanied by an adaptive depletion in CpG composition presumed to be linked to the action of antiviral mechanisms in these ancestral bat hosts. The closest bat virus to SARS-CoV-2, RmYN02 (sharing an ancestor about 1976), is a recombinant with a structure that includes differential CpG content in Spike; clear evidence of coinfection and evolution in bats without involvement of other species. While an undiscovered "facilitating" intermediate species cannot be discounted, collectively, our results support the progenitor of SARS-CoV-2 being capable of efficient human-human transmission as a consequence of its adaptive evolutionary history in bats, not humans, which created a relatively generalist virus.

Journal ArticleDOI
TL;DR: The Folding@home distributed computing project as mentioned in this paper was used to simulate the SARS-CoV-2 proteome and reveal dramatic conformational changes across the proteome, revealing over 50 'cryptic' pockets that expand targeting options for the design of antivirals.
Abstract: SARS-CoV-2 has intricate mechanisms for initiating infection, immune evasion/suppression and replication that depend on the structure and dynamics of its constituent proteins. Many protein structures have been solved, but far less is known about their relevant conformational changes. To address this challenge, over a million citizen scientists banded together through the Folding@home distributed computing project to create the first exascale computer and simulate 0.1 seconds of the viral proteome. Our adaptive sampling simulations predict dramatic opening of the apo spike complex, far beyond that seen experimentally, explaining and predicting the existence of 'cryptic' epitopes. Different spike variants modulate the probabilities of open versus closed structures, balancing receptor binding and immune evasion. We also discover dramatic conformational changes across the proteome, which reveal over 50 'cryptic' pockets that expand targeting options for the design of antivirals. All data and models are freely available online, providing a quantitative structural atlas.

Journal ArticleDOI
TL;DR: In this article, the authors analyzed microplastic concentration reported in 196 studies from 49 countries or territories from all continents and found that micro-plastic concentrations in soils or sediments and surface water could vary by up to eight orders of magnitude.


Journal ArticleDOI
TL;DR: This paper review and summarize the state-of-the-art methodologies for operation and control of NMGs, and introduces the opportunities, challenges, and possible solutions regarding N MGs for improving grid resilience, robustness, and efficiency.
Abstract: Networked microgrids (NMGs) are clusters of microgrids that are physically connected and functionally interoperable The massive and unprecedented deployment of smart grid technologies, new business models, and involvement of new stakeholders enable NMGs to be a conceptual operation paradigm for future distribution systems Much work needs to be done, however, to enable NMGs to achieve seamless coordination, including physical, communication, and functional integration In this paper, we review and summarize the state-of-the-art methodologies for operation and control of NMGs We also specifically discuss the notion of dynamic boundaries for advanced microgrid applications In addition, we introduce the opportunities, challenges, and possible solutions regarding NMGs for improving grid resilience, robustness, and efficiency

Journal ArticleDOI
TL;DR: In this paper, a doctoral fellowship supported by the Agencia Canaria de la Investigación, Innovación y Sociedad de la Información and the European Social Fund (Operational Programme of the Canary Islands 2014-2020) was used to support the DLW project.
Abstract: DLW was funded by ARC DECRA award # DE140101675 and supported by subsidy funding to OIST. NJM was funded by Marsden grants 16‐UOA‐277 and 18‐UOA‐034, and U. Auckland FRDF #3722433. JCP is funded by a doctoral fellowship supported by the Agencia Canaria de la Investigacion, Innovacion y Sociedad de la Informacion and the European Social Fund (Operational Programme of the Canary Islands 2014‐2020). MC acknowledges support from Australian Research Council Discovery Project DP110103168.

Journal ArticleDOI
12 Oct 2021-JAMA
TL;DR: In a repeated cross-sectional study conducted each month during July 2020 through May 2021, 17 blood collection organizations with blood donations from all 50 US states; Washington, DC; and Puerto Rico were organized into 66 study-specific regions, representing a catchment of 74% of the US population.
Abstract: Importance People who have been infected with or vaccinated against SARS-CoV-2 have reduced risk of subsequent infection, but the proportion of people in the US with SARS-CoV-2 antibodies from infection or vaccination is uncertain. Objective To estimate trends in SARS-CoV-2 seroprevalence related to infection and vaccination in the US population. Design, Setting, and Participants In a repeated cross-sectional study conducted each month during July 2020 through May 2021, 17 blood collection organizations with blood donations from all 50 US states; Washington, DC; and Puerto Rico were organized into 66 study-specific regions, representing a catchment of 74% of the US population. For each study region, specimens from a median of approximately 2000 blood donors were selected and tested each month; a total of 1 594 363 specimens were initially selected and tested. The final date of blood donation collection was May 31, 2021. Exposure Calendar time. Main Outcomes and Measures Proportion of persons with detectable SARS-CoV-2 spike and nucleocapsid antibodies. Seroprevalence was weighted for demographic differences between the blood donor sample and general population. Infection-induced seroprevalence was defined as the prevalence of the population with both spike and nucleocapsid antibodies. Combined infection- and vaccination-induced seroprevalence was defined as the prevalence of the population with spike antibodies. The seroprevalence estimates were compared with cumulative COVID-19 case report incidence rates. Results Among 1 443 519 specimens included, 733 052 (50.8%) were from women, 174 842 (12.1%) were from persons aged 16 to 29 years, 292 258 (20.2%) were from persons aged 65 years and older, 36 654 (2.5%) were from non-Hispanic Black persons, and 88 773 (6.1%) were from Hispanic persons. The overall infection-induced SARS-CoV-2 seroprevalence estimate increased from 3.5% (95% CI, 3.2%-3.8%) in July 2020 to 20.2% (95% CI, 19.9%-20.6%) in May 2021; the combined infection- and vaccination-induced seroprevalence estimate in May 2021 was 83.3% (95% CI, 82.9%-83.7%). By May 2021, 2.1 SARS-CoV-2 infections (95% CI, 2.0-2.1) per reported COVID-19 case were estimated to have occurred. Conclusions and Relevance Based on a sample of blood donations in the US from July 2020 through May 2021, vaccine- and infection-induced SARS-CoV-2 seroprevalence increased over time and varied by age, race and ethnicity, and geographic region. Despite weighting to adjust for demographic differences, these findings from a national sample of blood donors may not be representative of the entire US population.

Journal ArticleDOI
20 Jul 2021-JAMA
TL;DR: In this article, the authors evaluated the efficacy of canakinumab, an anti-interleukin-1β antibody, in patients hospitalized with severe COVID-19.
Abstract: Importance Effective treatments for patients with severe COVID-19 are needed. Objective To evaluate the efficacy of canakinumab, an anti–interleukin-1β antibody, in patients hospitalized with severe COVID-19. Design, Setting, and Participants This randomized, double-blind, placebo-controlled phase 3 trial was conducted at 39 hospitals in Europe and the United States. A total of 454 hospitalized patients with COVID-19 pneumonia, hypoxia (not requiring invasive mechanical ventilation [IMV]), and systemic hyperinflammation defined by increased blood concentrations of C-reactive protein or ferritin were enrolled between April 30 and August 17, 2020, with the last assessment of the primary end point on September 22, 2020. Intervention Patients were randomly assigned 1:1 to receive a single intravenous infusion of canakinumab (450 mg for body weight of 40- 80 kg; n = 227) or placebo (n = 227). Main Outcomes and Measures The primary outcome was survival without IMV from day 3 to day 29. Secondary outcomes were COVID-19–related mortality, measurements of biomarkers of systemic hyperinflammation, and safety evaluations. Results Among 454 patients who were randomized (median age, 59 years; 187 women [41.2%]), 417 (91.9%) completed day 29 of the trial. Between days 3 and 29, 198 of 223 patients (88.8%) survived without requiring IMV in the canakinumab group and 191 of 223 (85.7%) in the placebo group, with a rate difference of 3.1% (95% CI, −3.1% to 9.3%) and an odds ratio of 1.39 (95% CI, 0.76 to 2.54;P = .29). COVID-19–related mortality occurred in 11 of 223 patients (4.9%) in the canakinumab group vs 16 of 222 (7.2%) in the placebo group, with a rate difference of −2.3% (95% CI, −6.7% to 2.2%) and an odds ratio of 0.67 (95% CI, 0.30 to 1.50). Serious adverse events were observed in 36 of 225 patients (16%) treated with canakinumab vs 46 of 223 (20.6%) who received placebo. Conclusions and Relevance Among patients hospitalized with severe COVID-19, treatment with canakinumab, compared with placebo, did not significantly increase the likelihood of survival without IMV at day 29. Trial Registration ClinicalTrials.gov Identifier:NCT04362813

Journal ArticleDOI
TL;DR: Small, prospective associations of depression and inflammatory biomarkers are observed in both directions, particularly for IL-6; however, the strength and importance of this relationship is likely obscured by the heterogeneity in depression and profound study/methodological differences.
Abstract: The innate immune system is dysregulated in depression; however, less is known about the longitudinal associations of depression and inflammatory biomarkers. We investigated the prospective associations of depression and inflammatory biomarkers [interleukin-6 (IL-6), Tumor Necrosis Factor-Alpha (TNF-α), and C-reactive protein (CRP)] in community samples, both unadjusted and adjusted for covariates. The review, registered with PROSPERO, searched for published and unpublished studies via MEDLINE/PsycINFO/PsycARTICLES/EMBASE/Proquest Dissertation. Standardized Fisher transformations of the correlation/beta coefficients, both unadjusted and adjusted for covariates, were extracted from studies examining the prospective associations of depression and inflammatory biomarkers. Systematic review conducted in January, 2019 included 38 studies representing 58,256 participants, with up to 27 studies included in random-effects meta-analysis. Higher CRP/IL-6 were associated with future depressive symptoms, and higher depressive symptoms were associated with higher future CRP/IL-6 in both unadjusted and adjusted analyses - this is the first meta-analysis reporting an adjusted association of IL-6 with future depression. The adjusted prospective associations of depression with CRP/CRP with depression were substantially attenuated and small in magnitude. No significant associations were observed for TNF-α. No conclusive results were observed in studies of clinical depression. Meta-regression indicated that the association of CRP and future depression was larger in older samples and in studies not controlling for possible infection. Small, prospective associations of depression and inflammatory biomarkers are observed in both directions, particularly for IL-6; however, the strength and importance of this relationship is likely obscured by the heterogeneity in depression and profound study/methodological differences. Implications for future studies are discussed.

Journal ArticleDOI
TL;DR: In this paper, the authors investigated whether olfactory loss is a reliable predictor of COVID-19 using a crowdsourced questionnaire in 23 languages to assess symptoms in individuals self-reporting recent respiratory illness.
Abstract: In a preregistered, cross-sectional study, we investigated whether olfactory loss is a reliable predictor of COVID-19 using a crowdsourced questionnaire in 23 languages to assess symptoms in individuals self-reporting recent respiratory illness. We quantified changes in chemosensory abilities during the course of the respiratory illness using 0-100 visual analog scales (VAS) for participants reporting a positive (C19+; n = 4148) or negative (C19-; n = 546) COVID-19 laboratory test outcome. Logistic regression models identified univariate and multivariate predictors of COVID-19 status and post-COVID-19 olfactory recovery. Both C19+ and C19- groups exhibited smell loss, but it was significantly larger in C19+ participants (mean ± SD, C19+: -82.5 ± 27.2 points; C19-: -59.8 ± 37.7). Smell loss during illness was the best predictor of COVID-19 in both univariate and multivariate models (ROC AUC = 0.72). Additional variables provide negligible model improvement. VAS ratings of smell loss were more predictive than binary chemosensory yes/no-questions or other cardinal symptoms (e.g., fever). Olfactory recovery within 40 days of respiratory symptom onset was reported for ~50% of participants and was best predicted by time since respiratory symptom onset. We find that quantified smell loss is the best predictor of COVID-19 amongst those with symptoms of respiratory illness. To aid clinicians and contact tracers in identifying individuals with a high likelihood of having COVID-19, we propose a novel 0-10 scale to screen for recent olfactory loss, the ODoR-19. We find that numeric ratings ≤2 indicate high odds of symptomatic COVID-19 (4 < OR < 10). Once independently validated, this tool could be deployed when viral lab tests are impractical or unavailable.